Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 332 (6028): 484-488

Copyright © 2011 by the American Association for the Advancement of Science

Proteoglycan-Specific Molecular Switch for RPTP{sigma} Clustering and Neuronal Extension

Charlotte H. Coles,1,* Yingjie Shen,2,* Alan P. Tenney,2,3,{dagger} Christian Siebold,1,{dagger} Geoffrey C. Sutton,1 Weixian Lu,1 John T. Gallagher,4,5 E. Yvonne Jones,1,{ddagger} John G. Flanagan,2,{ddagger} A. Radu Aricescu1,{ddagger}

Abstract: Heparan and chondroitin sulfate proteoglycans (HSPGs and CSPGs, respectively) regulate numerous cell surface signaling events, with typically opposite effects on cell function. CSPGs inhibit nerve regeneration through receptor protein tyrosine phosphatase sigma (RPTP{sigma}). Here we report that RPTP{sigma} acts bimodally in sensory neuron extension, mediating CSPG inhibition and HSPG growth promotion. Crystallographic analyses of a shared HSPG-CSPG binding site reveal a conformational plasticity that can accommodate diverse glycosaminoglycans with comparable affinities. Heparan sulfate and analogs induced RPTP{sigma} ectodomain oligomerization in solution, which was inhibited by chondroitin sulfate. RPTP{sigma} and HSPGs colocalize in puncta on sensory neurons in culture, whereas CSPGs occupy the extracellular matrix. These results lead to a model where proteoglycans can exert opposing effects on neuronal extension by competing to control the oligomerization of a common receptor.

1 Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
2 Department of Cell Biology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
3 Motor Neuron Center, Columbia University, New York, NY 10032, USA.
4 School of Cancer and Imaging Sciences, Faculty of Medical and Health Sciences, University of Manchester, Paterson Institute for Cancer Research, Manchester M20 4BX, UK.
5 Iduron, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 4BX, UK.

* These authors contributed equally to this work.

{dagger} These authors contributed equally to this work.

{ddagger} To whom correspondence should be addressed. E-mail: radu{at} (A.R.A.); flanagan{at} (J.G.F.); yvonne{at} (E.Y.J.)

Structural insights into proteoglycan-shaped Hedgehog signaling.
D. M. Whalen, T. Malinauskas, R. J. C. Gilbert, and C. Siebold (2013)
PNAS 110, 16420-16425
   Abstract »    Full Text »    PDF »
Semaphorin 3A Binds to the Perineuronal Nets via Chondroitin Sulfate Type E Motifs in Rodent Brains.
G. Dick, C. L. Tan, J. N. Alves, E. M. E. Ehlert, G. M. Miller, L. C. Hsieh-Wilson, K. Sugahara, A. Oosterhof, T. H. van Kuppevelt, J. Verhaagen, et al. (2013)
J. Biol. Chem. 288, 27384-27395
   Abstract »    Full Text »    PDF »
The {delta}2 glutamate receptor gates long-term depression by coordinating interactions between two AMPA receptor phosphorylation sites.
K. Kohda, W. Kakegawa, S. Matsuda, T. Yamamoto, H. Hirano, and M. Yuzaki (2013)
PNAS 110, E948-E957
   Abstract »    Full Text »    PDF »
Insulin-Like Growth Factor (IGF) Binding Protein 2 Functions Coordinately with Receptor Protein Tyrosine Phosphatase {beta} and the IGF-I Receptor To Regulate IGF-I-Stimulated Signaling.
X. Shen, G. Xi, L. A. Maile, C. Wai, C. J. Rosen, and D. R. Clemmons (2012)
Mol. Cell. Biol. 32, 4116-4130
   Abstract »    Full Text »    PDF »
Processing of Neuregulin-1 by Neuropsin Regulates GABAergic Neuron to Control Neural Plasticity of the Mouse Hippocampus.
H. Tamura, M. Kawata, S. Hamaguchi, Y. Ishikawa, and S. Shiosaka (2012)
J. Neurosci. 32, 12657-12672
   Abstract »    Full Text »    PDF »
Mouse development is not obviously affected by the absence of dermatan sulfate epimerase 2 in spite of a modified brain dermatan sulfate composition.
B. Bartolini, M. A. Thelin, U. Rauch, R. Feinstein, A. Oldberg, A. Malmstrom, and M. Maccarana (2012)
Glycobiology 22, 1007-1016
   Abstract »    Full Text »    PDF »
Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats.
J. J. Hill, K. Jin, X. O. Mao, L. Xie, and D. A. Greenberg (2012)
PNAS 109, 9155-9160
   Abstract »    Full Text »    PDF »
Keratan Sulfate Proteoglycans in Plasticity and Recovery after Spinal Cord Injury.
B. J. Hilton, B. T. Lang, and J. M. Cregg (2012)
J. Neurosci. 32, 4331-4333
   Full Text »    PDF »
Keratan Sulfate Restricts Neural Plasticity after Spinal Cord Injury.
S. Imagama, K. Sakamoto, R. Tauchi, R. Shinjo, T. Ohgomori, Z. Ito, H. Zhang, Y. Nishida, N. Asami, S. Takeshita, et al. (2011)
J. Neurosci. 31, 17091-17102
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882